HRP990107A2 - Process for preparing phenoxyphenylsulfonyl halides - Google Patents
Process for preparing phenoxyphenylsulfonyl halides Download PDFInfo
- Publication number
- HRP990107A2 HRP990107A2 HR60/081,393A HRP990107A HRP990107A2 HR P990107 A2 HRP990107 A2 HR P990107A2 HR P990107 A HRP990107 A HR P990107A HR P990107 A2 HRP990107 A2 HR P990107A2
- Authority
- HR
- Croatia
- Prior art keywords
- formula
- alkyl
- compound
- fluorophenoxy
- solvent
- Prior art date
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- -1 phenoxyphenylsulfonyl halides Chemical class 0.000 title description 19
- 238000004519 manufacturing process Methods 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 56
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 41
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 30
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 29
- 239000002904 solvent Substances 0.000 claims description 25
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 21
- 239000011734 sodium Substances 0.000 claims description 19
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 18
- 125000001153 fluoro group Chemical group F* 0.000 claims description 18
- 125000001246 bromo group Chemical group Br* 0.000 claims description 16
- 229910052708 sodium Inorganic materials 0.000 claims description 16
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 15
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical group CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 229910052700 potassium Inorganic materials 0.000 claims description 13
- 238000002360 preparation method Methods 0.000 claims description 13
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical group ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 12
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 8
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 8
- 229910052744 lithium Inorganic materials 0.000 claims description 8
- 229910003202 NH4 Inorganic materials 0.000 claims description 7
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical group [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 230000002140 halogenating effect Effects 0.000 claims description 5
- 229910052749 magnesium Inorganic materials 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- 239000000243 solution Substances 0.000 description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- 239000002585 base Substances 0.000 description 18
- 239000000203 mixture Substances 0.000 description 16
- 150000003839 salts Chemical class 0.000 description 16
- 239000002253 acid Substances 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- HGMRCAGQEDXAGL-UHFFFAOYSA-N 1-[(3-ethoxy-3-oxopropyl)-[4-(4-fluorophenoxy)phenyl]sulfonylamino]cyclopentane-1-carboxylic acid Chemical compound C=1C=C(OC=2C=CC(F)=CC=2)C=CC=1S(=O)(=O)N(CCC(=O)OCC)C1(C(O)=O)CCCC1 HGMRCAGQEDXAGL-UHFFFAOYSA-N 0.000 description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- 102000029816 Collagenase Human genes 0.000 description 9
- 108060005980 Collagenase Proteins 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 229960002424 collagenase Drugs 0.000 description 9
- 239000003112 inhibitor Substances 0.000 description 9
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- 229940124761 MMP inhibitor Drugs 0.000 description 7
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 6
- 102000002274 Matrix Metalloproteinases Human genes 0.000 description 6
- 108010000684 Matrix Metalloproteinases Proteins 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 5
- VHHGUBHZBLPTKL-UHFFFAOYSA-N Cp-471358 Chemical compound C=1C=C(OC=2C=CC(F)=CC=2)C=CC=1S(=O)(=O)N(CCC(O)=O)C1(C(=O)NO)CCCC1 VHHGUBHZBLPTKL-UHFFFAOYSA-N 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 239000011777 magnesium Substances 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 235000019198 oils Nutrition 0.000 description 5
- WRHVOZDHNZPGNO-UHFFFAOYSA-N 4-(4-fluorophenoxy)benzenesulfonic acid Chemical compound C1=CC(S(=O)(=O)O)=CC=C1OC1=CC=C(F)C=C1 WRHVOZDHNZPGNO-UHFFFAOYSA-N 0.000 description 4
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical class C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- 102000004142 Trypsin Human genes 0.000 description 4
- 108090000631 Trypsin Proteins 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 238000011065 in-situ storage Methods 0.000 description 4
- 229940121386 matrix metalloproteinase inhibitor Drugs 0.000 description 4
- 239000003771 matrix metalloproteinase inhibitor Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000012588 trypsin Substances 0.000 description 4
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 3
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 description 3
- PDAYRCHIAPCRRD-UHFFFAOYSA-N 4-(4-fluorophenoxy)benzenesulfonyl chloride Chemical compound C1=CC(F)=CC=C1OC1=CC=C(S(Cl)(=O)=O)C=C1 PDAYRCHIAPCRRD-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 3
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- ICKPCMLGESBARJ-UHFFFAOYSA-N benzyl 1-[[4-(4-fluorophenoxy)phenyl]sulfonylamino]cyclopentane-1-carboxylate Chemical compound C1=CC(F)=CC=C1OC1=CC=C(S(=O)(=O)NC2(CCCC2)C(=O)OCC=2C=CC=CC=2)C=C1 ICKPCMLGESBARJ-UHFFFAOYSA-N 0.000 description 3
- 150000001768 cations Chemical class 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 229940088598 enzyme Drugs 0.000 description 3
- ZCVWLNIALLKWDO-UHFFFAOYSA-N ethyl 3-[(1-carbonochloridoylcyclopentyl)-[4-(4-fluorophenoxy)phenyl]sulfonylamino]propanoate Chemical compound C=1C=C(OC=2C=CC(F)=CC=2)C=CC=1S(=O)(=O)N(CCC(=O)OCC)C1(C(Cl)=O)CCCC1 ZCVWLNIALLKWDO-UHFFFAOYSA-N 0.000 description 3
- LLMCVPDKPNDQCK-UHFFFAOYSA-N ethyl 3-[[4-(4-fluorophenoxy)phenyl]sulfonyl-[1-(hydroxycarbamoyl)cyclopentyl]amino]propanoate Chemical compound C=1C=C(OC=2C=CC(F)=CC=2)C=CC=1S(=O)(=O)N(CCC(=O)OCC)C1(C(=O)NO)CCCC1 LLMCVPDKPNDQCK-UHFFFAOYSA-N 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- RFPOAIKHXKNFPZ-UHFFFAOYSA-N (4-fluorophenyl) 4-(4-fluorophenoxy)benzenesulfonate Chemical compound C1=CC(F)=CC=C1OC1=CC=C(S(=O)(=O)OC=2C=CC(F)=CC=2)C=C1 RFPOAIKHXKNFPZ-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- 102100027995 Collagenase 3 Human genes 0.000 description 2
- 108050005238 Collagenase 3 Proteins 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical group [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 229940124639 Selective inhibitor Drugs 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 150000001447 alkali salts Chemical class 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 150000004703 alkoxides Chemical class 0.000 description 2
- 230000033115 angiogenesis Effects 0.000 description 2
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- 206010003246 arthritis Diseases 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 239000013068 control sample Substances 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 201000008482 osteoarthritis Diseases 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- 239000011591 potassium Chemical group 0.000 description 2
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- 238000000746 purification Methods 0.000 description 2
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- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 2
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- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 1
- FFUBAZZKSHAKEL-UHFFFAOYSA-N 1-[(3-ethoxy-3-oxoprop-1-enyl)-[4-(4-fluorophenoxy)phenyl]sulfonylamino]cyclopentane-1-carboxylic acid Chemical compound C=1C=C(OC=2C=CC(F)=CC=2)C=CC=1S(=O)(=O)N(C=CC(=O)OCC)C1(C(O)=O)CCCC1 FFUBAZZKSHAKEL-UHFFFAOYSA-N 0.000 description 1
- DGJCJAUTUPRYNU-UHFFFAOYSA-N 1-[[4-(4-fluorophenoxy)phenyl]sulfonylamino]cyclopentane-1-carboxylic acid Chemical compound C=1C=C(OC=2C=CC(F)=CC=2)C=CC=1S(=O)(=O)NC1(C(=O)O)CCCC1 DGJCJAUTUPRYNU-UHFFFAOYSA-N 0.000 description 1
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- UIIJZQVROQHLAP-UHFFFAOYSA-N 2-methyl-2-(2-methylbutan-2-yloxy)butane;sodium Chemical compound [Na].CCC(C)(C)OC(C)(C)CC UIIJZQVROQHLAP-UHFFFAOYSA-N 0.000 description 1
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- GZLPFEYTAAXJCP-UHFFFAOYSA-N 3,5-dimethyl-1,2-oxazole-4-sulfonyl chloride Chemical group CC1=NOC(C)=C1S(Cl)(=O)=O GZLPFEYTAAXJCP-UHFFFAOYSA-N 0.000 description 1
- CZIZTCRBMDZZLZ-UHFFFAOYSA-N 3-[(1-carbonochloridoylcyclopentyl)-[4-(4-fluorophenoxy)phenyl]sulfonylamino]propanoic acid Chemical compound C=1C=C(OC=2C=CC(F)=CC=2)C=CC=1S(=O)(=O)N(CCC(=O)O)C1(C(Cl)=O)CCCC1 CZIZTCRBMDZZLZ-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-M 3-carboxy-2,3-dihydroxypropanoate Chemical compound OC(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-M 0.000 description 1
- ZNBNBTIDJSKEAM-UHFFFAOYSA-N 4-[7-hydroxy-2-[5-[5-[6-hydroxy-6-(hydroxymethyl)-3,5-dimethyloxan-2-yl]-3-methyloxolan-2-yl]-5-methyloxolan-2-yl]-2,8-dimethyl-1,10-dioxaspiro[4.5]decan-9-yl]-2-methyl-3-propanoyloxypentanoic acid Chemical compound C1C(O)C(C)C(C(C)C(OC(=O)CC)C(C)C(O)=O)OC11OC(C)(C2OC(C)(CC2)C2C(CC(O2)C2C(CC(C)C(O)(CO)O2)C)C)CC1 ZNBNBTIDJSKEAM-UHFFFAOYSA-N 0.000 description 1
- ZLYBFBAHAQEEQQ-UHFFFAOYSA-N 4-chlorobenzenesulfonyl chloride Chemical compound ClC1=CC=C(S(Cl)(=O)=O)C=C1 ZLYBFBAHAQEEQQ-UHFFFAOYSA-N 0.000 description 1
- RHMPLDJJXGPMEX-UHFFFAOYSA-N 4-fluorophenol Chemical compound OC1=CC=C(F)C=C1 RHMPLDJJXGPMEX-UHFFFAOYSA-N 0.000 description 1
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- ORILYTVJVMAKLC-UHFFFAOYSA-N Adamantane Natural products C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 description 1
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- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical group [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C301/00—Esters of sulfurous acid
- C07C301/02—Esters of sulfurous acid having sulfite groups bound to carbon atoms of six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/02—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
- C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/41—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing singly-bound oxygen atoms bound to the carbon skeleton
- C07C309/42—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing singly-bound oxygen atoms bound to the carbon skeleton having the sulfo groups bound to carbon atoms of non-condensed six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/63—Esters of sulfonic acids
- C07C309/72—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/75—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing singly-bound oxygen atoms bound to the carbon skeleton
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Physical Education & Sports Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Description
Tehnički problem Technical problem
Ovaj izum se odnosi na postupak za pripravu fenoksifenilsulfonil halogenida, koji su korisni međuprodukti za dobivanje inhibitora matriks metaloproteinaze i na njihove međuprodukte. This invention relates to a process for the preparation of phenoxyphenylsulfonyl halides, which are useful intermediates for obtaining matrix metalloproteinase inhibitors, and to their intermediates.
Inhibitori matriks metaloproteinaze (MMP) su poznati kao korisni u liječenju stanja odabranog iz skupine koju čine artritis (uključujući osteoartritis i reumatoidni artritis), upalna bolest crijeva, Crohn-ova bolest, emfizem, akutni respiratorni distres sindrom, astma, kronična opstruktivna plućna bolest, Alzheimer-ova bolest, toksičnost presađenog organa, kaheksija, alergijske reakcije, alergijska kontaktna hipersenzitivnost, rak, ulceracija tkiva, restenoza, bolest periodonta, bulozna epidermoliza, osteoporoza, popuštanje usadaka umjetnih zglobova, ateroskleroza (uključujući rupturu aterosklerotične naslage), aneurizma aorte (uključujući abdominalnu aneurizmu aorte i moždanu aneurizmu), kongestivno zatajenje srca, infarkt miokarda, kap, cerebralna ishemija, trauma glave, ozljeda kralježnične moždine, neuro-degenerativni poremećaji (akutni i kronični), autoimuni poremećaji, Huntington-ova bolest, Parkinson-ova bolest, migrena, depresija, periferna neuropatija, bol, cerebralna amiloidna angiopatija, nootropsko ili spoznajno pojačanje, amiotrofična lateralna skleroza, multipla skleroza, očna angiogeneza, ozljeda rožnice, makularna degeneracija, abnormalno cijeljenje rana, opekotine, dijabetes, invazija tumora, rast tumora, metastaza tumora, ožiljkivanje rožnice, skleritis, AIDS, sepsa, septički šok i druge bolesti karakterizirane inhibicijom metaloproteinaze ili ekspresijom ADAM (uključujući TNF-α). U dodatku, proizvodi koji se mogu pripraviti od spojeva i postupaka iz ovog izuma mogu se upotrijebiti u kombiniranoj terapiji sa standardnim nesteroidnim antiinflamatornim lijekovima (dalje u tekstu NSAID, non-steroidal anti-inflammatory drugs), COX-2 inhibitorima i analgeticima u liječenju artritisa, i u kombinaciji sa citotoksičnim lijekovima kao što su adriamicin, daunomicin, cis-platinum, etopozid, taksol, taksoter i alkaloidi, kao vinkristin, u liječenju raka. Matrix metalloproteinase (MMP) inhibitors are known to be useful in the treatment of conditions selected from the group consisting of arthritis (including osteoarthritis and rheumatoid arthritis), inflammatory bowel disease, Crohn's disease, emphysema, acute respiratory distress syndrome, asthma, chronic obstructive pulmonary disease, Alzheimer's disease, organ transplant toxicity, cachexia, allergic reactions, allergic contact hypersensitivity, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, osteoporosis, joint graft loosening, atherosclerosis (including rupture of atherosclerotic plaque), aortic aneurysm (including abdominal aortic aneurysm and brain aneurysm), congestive heart failure, myocardial infarction, stroke, cerebral ischemia, head trauma, spinal cord injury, neuro-degenerative disorders (acute and chronic), autoimmune disorders, Huntington's disease, Parkinson's disease, migraine, depression, peripheral neuropathy, pain, cerebral amyloidn and angiopathy, nootropic or cognitive enhancement, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration, abnormal wound healing, burns, diabetes, tumor invasion, tumor growth, tumor metastasis, corneal scarring, scleritis, AIDS, sepsis, septic shock and other diseases characterized by metalloproteinase inhibition or ADAM expression (including TNF-α). In addition, the products that can be prepared from the compounds and methods of the present invention can be used in combination therapy with standard non-steroidal anti-inflammatory drugs (NSAID, non-steroidal anti-inflammatory drugs), COX-2 inhibitors and analgesics in the treatment of arthritis. , and in combination with cytotoxic drugs such as adriamycin, daunomycin, cis-platinum, etoposide, taxol, taxotere and alkaloids, such as vincristine, in the treatment of cancer.
Inhibitori matriks metaloproteinaze dobro su poznati u literaturi. Specifično, PCT publikacija WO 96/33172 objavljena 24. listopada 1996., odnosi se na cikličke arilsulfonilamino hidroksaminske kiseline koje se koriste kao MMP inhibitori. US patent br. 5.672.615, PCT publikacija WO 97/20824, PCT publikacija WO 98/08825, PCT publikacija WO 98/27069, i PCT publikacija WO 98/34918, objavljeni 13. kolovoza 1998., naslovljeni "Derivati arilsulfonil hidroksaminske kiseline" se svi odnose na cikličke hidroksaminske kiseline koje se koriste kao MMP inhibitori. PCT publikacije WO 96/27583 i WO 98/07697, objavljene 7. ožujka 1996. i 26. veljače 1998., pojedinačno se odnose na arilsulfonil hidroksaminske kiseline. PCT publikacija WO 98/03516, objavljena 29. siječnja 1998., odnosi se na fosfinate sa MMP aktivnošću. PCT publikacija WO 98/34915, objavljena 13. kolovoza 1998., naslovljena "Derivati N-hidroksi-�-sulfonil propionamida", odnosi se na propionilhidroksamide kao korisne MMP inhibitore. PCT publikacija WO 98/33768, objavljena 6. kolovoza 1998., naslovljena "Derivati arilsulfonilamino hidroksaminske kiseline", odnosi se na N-nesupstituirane arilsulfonilamino hidroksaminske kiseline. PCT publikacija WO 98/30566, objavljena 16. srpnja 1998., naslovljena "Derivati cikličkih sulfona", odnosi se na cikličke sulfon hidroksaminske kiseline kao MMP inhibitore. Privremena patentna prijava u SAD br. 60/55208, prijavljena 8. kolovoza 1997., odnosi se na biaril hidroksaminske kiseline kao MMP inhibitore. Privremena patentna prijava u SAD br. 60/55207, prijavljena 8. kolovoza 1997., naslovljena "Derivati ariloksiarilsulfonilamino hidroksaminske kiseline", odnosi se na ariloksiarilsulfonil hidroksaminske kiseline kao MMP inhibitore. Privremena patentna prijava u SAD br. 60/62766, prijavljena 24. listopada 1997., naslovljena "Upotreba MMP-13 selektivnih inhibitora u liječenju osteoartritisa i drugih MMP posredovanih poremećaja", odnosi se na upotrebu MMP-13 selektivnih inhibitora u liječenju upale i drugih poremećaja. Privremena patentna prijava u SAD br. 60/68261, prijavljena 19. prosinca 1997., odnosi se na upotrebu MMP inhibitora u liječenju angiogeneze i drugih poremećaja. Svaka od gore navedenih publikacija i prijava ovdje je u svojoj cijelosti uklopljena po referenci. Matrix metalloproteinase inhibitors are well known in the literature. Specifically, PCT publication WO 96/33172 published October 24, 1996, relates to cyclic arylsulfonylamino hydroxamic acids for use as MMP inhibitors. US patent no. 5,672,615, PCT Publication WO 97/20824, PCT Publication WO 98/08825, PCT Publication WO 98/27069, and PCT Publication WO 98/34918, published Aug. 13, 1998, entitled "Arylsulfonyl Hydroxamic Acid Derivatives" all relate to to cyclic hydroxamic acids used as MMP inhibitors. PCT Publications WO 96/27583 and WO 98/07697, published March 7, 1996 and February 26, 1998, respectively, relate to arylsulfonyl hydroxamic acids. PCT Publication WO 98/03516, published January 29, 1998, relates to phosphinates with MMP activity. PCT Publication WO 98/34915, published August 13, 1998, entitled "N-hydroxy--sulfonyl propionamide derivatives", relates to propionylhydroxamides as useful MMP inhibitors. PCT Publication WO 98/33768, published August 6, 1998, entitled "Arylsulfonylamino hydroxamic acid derivatives", relates to N-unsubstituted arylsulfonylamino hydroxamic acids. PCT Publication WO 98/30566, published July 16, 1998, entitled "Cyclic Sulphone Derivatives", relates to cyclic hydroxamic acid sulfones as MMP inhibitors. US Provisional Patent Application No. 60/55208, filed Aug. 8, 1997, relates to biaryl hydroxamic acids as MMP inhibitors. US Provisional Patent Application No. 60/55207, filed Aug. 8, 1997, entitled "Aryloxyarylsulfonylamino hydroxamic acid derivatives", relates to aryloxyarylsulfonyl hydroxamic acid as MMP inhibitors. US Provisional Patent Application No. 60/62766, filed Oct. 24, 1997, entitled "Use of MMP-13 selective inhibitors in the treatment of osteoarthritis and other MMP-mediated disorders", relates to the use of MMP-13 selective inhibitors in the treatment of inflammation and other disorders. US Provisional Patent Application No. 60/68261, filed Dec. 19, 1997, relates to the use of MMP inhibitors in the treatment of angiogenesis and other disorders. Each of the above publications and applications is incorporated herein in its entirety by reference.
Sadašnji izumitelji su sada otkrili prikladan postupak za pripravu (4-fluorofenoksi-fenil)-sulfonil klorida u tri koraka iz 4-kloro-sulfonil klorida. The present inventors have now discovered a suitable process for the preparation of (4-fluorophenoxy-phenyl)-sulfonyl chloride in three steps from 4-chloro-sulfonyl chloride.
Bit izuma The essence of invention
Ovaj izum se odnosi na spoj formule This invention relates to a compound of the formula
[image] [image]
gdje R je H, Li, Na, K, Mg, ili NH4, poželjno Na, K, ili Mg, najpoželjnije Na. where R is H, Li, Na, K, Mg, or NH4, preferably Na, K, or Mg, most preferably Na.
Drugi poželjni spojevi iz izuma uključuju spojeve formule Other preferred compounds of the invention include compounds of the formula
[image] [image]
gdje m je cijeli broj od 1-3; where m is an integer from 1-3;
gdje R2 je fluoro, kloro, bromo, (C1-C6)alkil, (C1-C6)alkoksi ili perfluoro(C1-C3)alkil, poželjno fluoro, najpoželjnije gdje R2 je u 4-položaju fenilnog prstena. where R 2 is fluoro, chloro, bromo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or perfluoro(C 1 -C 3 )alkyl, preferably fluoro, most preferably where R 2 is in the 4-position of the phenyl ring.
Ovaj izum se također odnosi na postupak priprave spoja formule This invention also relates to a process for the preparation of a compound of the formula
[image] [image]
gdje m je cijeli broj od 1-3; where m is an integer from 1-3;
gdje R2 je fluoro, kloro, bromo, (C1-C6)alkil, (C1-C6)alkoksi ili perfluoro(C1-C3)alkil; where R 2 is fluoro, chloro, bromo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or perfluoro(C 1 -C 3 )alkyl;
koji sadrži reakciju spoja formule which contains the reaction of the compound of the formula
[image] [image]
gdje R3 je fluoro, kloro ili bromo; i R4 je kloro ili bromo; where R 3 is fluoro, chloro or bromo; and R 4 is chloro or bromo;
sa spojem formule with the compound formula
[image] [image]
gdje m je cijeli broj od 1-3, i R2 je fluoro, kloro, bromo, (C1-C6)alkil, (C1-C6)alkoksi ili perfluoro(C1-C3)alkil; where m is an integer from 1-3, and R 2 is fluoro, chloro, bromo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or perfluoro(C 1 -C 3 )alkyl;
u prisutnosti baze, poželjno kalij-t-butoksida, i otapala, poželjno N-metilpirolidinona, pri temperaturi od 0 °C do oko 150 °C. in the presence of a base, preferably potassium t-butoxide, and a solvent, preferably N-methylpyrrolidinone, at a temperature of from 0 °C to about 150 °C.
Ovaj izum se također odnosi na postupak koji sadrži reakciju spomenutog spoja formule III s bazom, poželjno natrij-hidroksidom, u otapalu, poželjno etanolu, pri temperaturi od oko 50 °C do oko 100 °C da nastane spoj formule This invention also relates to a process comprising reacting said compound of formula III with a base, preferably sodium hydroxide, in a solvent, preferably ethanol, at a temperature of about 50°C to about 100°C to form a compound of formula
[image] [image]
gdje R je H, Li, Na, K ili NH4, poželjno Na, K ili Mg, najpoželjnije Na; where R is H, Li, Na, K or NH4, preferably Na, K or Mg, most preferably Na;
m je cijeli broj od 1-3; i m is an integer from 1-3; and
R2 je fluoro, kloro, bromo, (C1-C6)alkil, (C1-C6)alkoksi ili perfluoro(C1-C3)alkil. R 2 is fluoro, chloro, bromo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl or perfluoro (C 1 -C 3 )alkyl.
Ovaj izum se također odnosi na postupak koji sadrži reakciju spoja formule This invention also relates to a process comprising the reaction of a compound of the formula
[image] [image]
gdje m je cijeli broj od 1-3; where m is an integer from 1-3;
R je H, Li, Na, K ili NH4, poželjno Na, K ili Mg, najpoželjnije Na; i R is H, Li, Na, K or NH4, preferably Na, K or Mg, most preferably Na; and
R2 je fluoro, kloro, bromo, (C1-C6)alkil, (C1-C6)alkoksi ili perfluoro(C1-C3)alkil; R 2 is fluoro, chloro, bromo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy or perfluoro(C 1 -C 3 )alkyl;
s halogenirajućim sredstvom, poželjno tionil-kloridom, u otapalu pri temperaturi od oko 0 °C do oko 80 °C da nastane spoj formule with a halogenating agent, preferably thionyl chloride, in a solvent at a temperature of about 0 °C to about 80 °C to form a compound of the formula
[image] [image]
gdje m je cijeli broj od 1-3; where m is an integer from 1-3;
R1 je halogenid, poželjno kloro, i R2 je fluoro, kloro, bromo, (C1-C6)alkil, (C1-C6)alkoksi ili perfluoro(C1-C3) alkil, poželjno fluoro, kloro, bromo, još poželjnije fluoro, najpoželjnije gdje R2 je u 4-položaju fenilnog prstena. Poželjno, spomenuta reakcija se izvodi u prisutnosti katalizatora, poželjno dimetilformamida, i otapala, poželjno toluena. R1 is a halide, preferably chloro, and R2 is fluoro, chloro, bromo, (C1-C6)alkyl, (C1-C6)alkoxy or perfluoro(C1-C3)alkyl, preferably fluoro, chloro, bromo, more preferably fluoro, most preferred where R 2 is in the 4-position of the phenyl ring. Preferably, said reaction is carried out in the presence of a catalyst, preferably dimethylformamide, and a solvent, preferably toluene.
Detaljan opis izuma Detailed description of the invention
Slijedeće reakcijske sheme ilustriraju pripravu spojeva iz ovog izuma. Ako nije drugačije naznačeno, R, R1, R2, R3 i R4 u reakcijskim shemama i diskusiji koja slijedi su kako je gore definirano. The following reaction schemes illustrate the preparation of the compounds of this invention. Unless otherwise indicated, R, R1, R2, R3 and R4 in the reaction schemes and discussion that follows are as defined above.
[image] [image]
[image] [image]
Shema 1 se odnosi na pripravu spoja formule I, gdje R1 je halogen. Spojevi formule I su korisni međuprodukti koji se mogu pretvoriti u inhibitore matriks metaloproteinaze formule IX prema metodama iz sheme 2. Scheme 1 relates to the preparation of a compound of formula I, where R1 is halogen. Compounds of formula I are useful intermediates that can be converted to matrix metalloproteinase inhibitors of formula IX according to the methods of Scheme 2.
Prema shemi 1, spoj formule I se dobiva iz spoja formule II reakcijom s halogenirajućim sredstvom, poželjno u prisutnosti otapala i katalizatora. Prikladna halogenirajuća sredstva uključuju oksalil-klorid, tionil-klorid, fosfor-oksiklorid ili fosfor-pentaklorid, poželjno tionil-klorid. Prikladni katalizatori uključuju dimetilformamid. Prikladna otapala uključuju toluen, metilen-klorid ili heksan, poželjno toluen. Spomenuta reakcija se izvodi pri temperaturi od oko 0 °C do oko 70 °C, poželjan raspon između 25 °C i oko 60 °C. According to scheme 1, the compound of formula I is obtained from the compound of formula II by reaction with a halogenating agent, preferably in the presence of a solvent and a catalyst. Suitable halogenating agents include oxalyl chloride, thionyl chloride, phosphorus oxychloride or phosphorus pentachloride, preferably thionyl chloride. Suitable catalysts include dimethylformamide. Suitable solvents include toluene, methylene chloride or hexane, preferably toluene. Said reaction is carried out at a temperature of about 0 °C to about 70 °C, the preferred range being between 25 °C and about 60 °C.
Spojevi formule II, gdje R je vodik, natrij, kalij ili amonij (tj. H, Li, Na, K ili NH4), poželjno natrij, mogu se dobiti iz spojeva formule II reakcijom s bazom u otapalu. Stručnjak će razumjeti da kad R je Li, Na, K ili NH4, spoj formule II je ionski, i skupina R ima pozitivni naboj, a susjedni atom kisika ima negativni naboj. Prikladne baze uključuju natrij-hidroksid, kalij-hidroksid ili amonij-hidroksid, poželjno natrij-hidroksid. Prikladna otapala uključuju alkohole kao npr. metanol, etanol, izopropanol, t-butanol ili voda i njihove smjese, poželjno etanol. Spomenuta reakcija se izvodi pri temperaturi od oko 0 °C do oko 100 °C, poželjan raspon između 60 °C do oko 80 °C. Compounds of formula II, where R is hydrogen, sodium, potassium or ammonium (ie H, Li, Na, K or NH4), preferably sodium, can be obtained from compounds of formula II by reaction with a base in a solvent. One skilled in the art will understand that when R is Li, Na, K or NH4, the compound of formula II is ionic, and the R group has a positive charge and the adjacent oxygen atom has a negative charge. Suitable bases include sodium hydroxide, potassium hydroxide or ammonium hydroxide, preferably sodium hydroxide. Suitable solvents include alcohols such as methanol, ethanol, isopropanol, t-butanol or water and mixtures thereof, preferably ethanol. Said reaction is carried out at a temperature of about 0 °C to about 100 °C, the preferred range being between 60 °C to about 80 °C.
Spoj formule III može se dobiti reakcijom spoja formule IV sa spojem formule V u prisutnosti baze u otapalu. Prikladne baze uključuju zasjenjene alkokside ili karbonatne baze kao npr. kalij-t-butoksid, natrij-t-amil oksid ili kalij-karbonat, poželjno kalij-t-butoksid. Još poželjnije, upotrebljavaju se dva ekvivalenta kalij-t-butoksida. Prikladna otapala uključuju N-metilpirolidinon, dimetil formamid, dimetilacetamid ili diglim, poželjno N-metil-pirolidinon. Spomenuta reakcija se izvodi pri temperaturi od oko 0 °C do oko 150 °C, poželjan raspon između 25 °C i oko 130 °C. Najpoželjnije je da se reakcija provodi pri temperaturi od oko 25 °C oko 1 sat i zatim se temperatura povisi na oko 130 °C oko 12 sati. A compound of formula III can be obtained by reacting a compound of formula IV with a compound of formula V in the presence of a base in a solvent. Suitable bases include shaded alkoxides or carbonate bases such as potassium t-butoxide, sodium t-amyl oxide or potassium carbonate, preferably potassium t-butoxide. More preferably, two equivalents of potassium t-butoxide are used. Suitable solvents include N-methylpyrrolidinone, dimethyl formamide, dimethylacetamide or diglyme, preferably N-methyl-pyrrolidinone. Said reaction is carried out at a temperature of about 0 °C to about 150 °C, the preferred range being between 25 °C and about 130 °C. It is most preferable that the reaction is carried out at a temperature of about 25 °C for about 1 hour and then the temperature is raised to about 130 °C for about 12 hours.
Spojevi formula IV i V su komercijalno dostupni ili se mogu pripremiti metodama poznatim stručnjacima. Compounds of formulas IV and V are commercially available or can be prepared by methods known to those skilled in the art.
Shema 2 se odnosi na pripravu spojeva inhibitora matriks metaloproteinaze formule XI, gdje R6 i R7 su kako je definirano za odgovarajuće skupine R2 i R3 u PCT publikacijama WO 96/27583 i WO 98/07697, objavljenim 7. ožujka 1996. i 26. veljače 1998., pojedinačno. Spojevi formule VI mogu se pripraviti prema PCT publikacijama WO 96/27583 i WO 98/07697, objavljenim 7. ožujka 1996. i 26. veljače 1998. Ove publikacije su ovdje u svojoj cijelosti uklopljene po referenci. Scheme 2 relates to the preparation of matrix metalloproteinase inhibitor compounds of formula XI, where R 6 and R 7 are as defined for the respective groups R 2 and R 3 in PCT publications WO 96/27583 and WO 98/07697, published March 7, 1996 and February 26, 1996 1998, individually. Compounds of formula VI can be prepared according to PCT Publications WO 96/27583 and WO 98/07697, published March 7, 1996 and February 26, 1998. These publications are hereby incorporated by reference in their entirety.
Prema shemi 2, spojevi spomenute formule XI se dobivaju iz spojeva formule IX reakcijom sa klorirajućim sredstvom kao npr. oksalil-klorid ili tionil-klorid, poželjno oksalil-klorid, i katalitičkom količinom, poželjno oko 2 %, N,N-dimetilformamida u inertnom otapalu kao npr. metilen-kloridu ili toluenu da nastane in situ kiselinski klorid formule X koji kasnije reagira sa in situ formiranim siliranim hidroksilaminom. Silirani hidroksilamin formiran in situ dobiva se reakcijom hidroksilamin hidroklorida ili hidroksilamin sulfata, poželjno hidroksilamin hidroklorida, sa trimetilsilil kloridom u prisutnosti baze kao što je piridin, 2,6-lutidin, ili diizopropiletilamin, poželjno piridin otapalo. Prikladni silirani hidroksilamin formiran in situ odabran je od O-trimetilsililhidroksilamina, N,O-bistrimetilsililhidroksilamina ili njihovih kombinacija. Reakcija se izvodi pri temperaturi od oko 0 °C do oko 22 °C (tj. sobnoj temperaturi) oko 1 do oko 12 sati, poželjno oko 1 sat. According to scheme 2, the compounds of the aforementioned formula XI are obtained from the compounds of the formula IX by reaction with a chlorinating agent such as, for example, oxalyl chloride or thionyl chloride, preferably oxalyl chloride, and a catalytic amount, preferably about 2%, of N,N-dimethylformamide in inert solvent such as methylene chloride or toluene to form in situ the acid chloride of formula X which later reacts with the in situ formed silylated hydroxylamine. Silated hydroxylamine formed in situ is obtained by reacting hydroxylamine hydrochloride or hydroxylamine sulfate, preferably hydroxylamine hydrochloride, with trimethylsilyl chloride in the presence of a base such as pyridine, 2,6-lutidine, or diisopropylethylamine, preferably a pyridine solvent. A suitable in situ formed silylated hydroxylamine is selected from O-trimethylsilylhydroxylamine, N,O-bistrimethylsilylhydroxylamine or combinations thereof. The reaction is carried out at a temperature of about 0°C to about 22°C (ie, room temperature) for about 1 to about 12 hours, preferably about 1 hour.
Spojevi formule IX mogu se pripraviti iz spojeva formule VIII redukcijom u polarnom otapalu. Prikladna reducirajuća sredstva uključuju paladijske katalizatore, kao što su vodik preko paladija, vodik preko paladija na ugljiku ili vodik preko paladij-hidroksida na ugljiku, poželjno vodik preko paladija na ugljiku. Prikladna otapala uključuju tetrahidrofuran, metanol, etanol i izopropanol i njihove smjese, poželjno etanol. Spomenuta reakcija se izvodi pri temperaturi od oko 22 °C (tj. sobnoj temperaturi) u periodu od 1 do 7 dana, poželjno oko 2 dana. Compounds of formula IX can be prepared from compounds of formula VIII by reduction in a polar solvent. Suitable reducing agents include palladium catalysts, such as hydrogen over palladium, hydrogen over palladium on carbon or hydrogen over palladium hydroxide on carbon, preferably hydrogen over palladium on carbon. Suitable solvents include tetrahydrofuran, methanol, ethanol and isopropanol and mixtures thereof, preferably ethanol. The mentioned reaction is carried out at a temperature of about 22 °C (ie room temperature) for a period of 1 to 7 days, preferably about 2 days.
Spojevi formule VIII mogu se dobiti od spojeva formule VII, gdje R5 je opcionalno supstituirani benzil, Michael-ovom adicijom na propiolatni ester uz bazu u polarnom otapalu. Prikladni propiolati su oni formule H-C≡C-CO2R8, gdje R8 je (C1-C6)alkil. Prikladne baze uključuju tetrabutilamonij-fluorid, kalij-karbonat, tercijarne amine i cezij-karbonat, poželjno tetrabutilamonij-fluorid. Prikladna otapala uključuju tetrahidrofuran, acetonitril, tert-butanol, t-amilne alkohole i N,N-dimetilformamid, poželjno tetrahidrofuran. Spomenuta reakcija se izvodi pri temperaturi od oko -10 °C do oko 60 °C, poželjan raspon između 0 °C i oko 22 °C (tj. sobna temperatura). Spojevi formule VIII se dobivaju kao smjese geometrijskih izomera oko olefinske dvostruke veze; separacija izomera nije nužna. Compounds of formula VIII can be obtained from compounds of formula VII, where R5 is optionally substituted benzyl, by Michael addition to a propiolate ester with a base in a polar solvent. Suitable propiolates are those of the formula H-C≡C-CO2R8, where R8 is (C1-C6)alkyl. Suitable bases include tetrabutylammonium fluoride, potassium carbonate, tertiary amines and cesium carbonate, preferably tetrabutylammonium fluoride. Suitable solvents include tetrahydrofuran, acetonitrile, tert-butanol, t-amyl alcohols and N,N-dimethylformamide, preferably tetrahydrofuran. Said reaction is carried out at a temperature of about -10°C to about 60°C, the preferred range being between 0°C and about 22°C (ie, room temperature). Compounds of formula VIII are obtained as mixtures of geometric isomers around an olefinic double bond; isomer separation is not necessary.
Spojevi formule VII mogu se dobiti reakcijom spojeva formule VI sa spojevima formule I, iz sheme 1, u prisutnosti baze u otapalu. Prikladne baze uključuju trietilamin, diizopropiletilamin, poželjno trietilamin. Prikladna otapala uključuju toluen, ili metilen-klorid, poželjno toluen. Compounds of formula VII can be obtained by reacting compounds of formula VI with compounds of formula I, from scheme 1, in the presence of a base in a solvent. Suitable bases include triethylamine, diisopropylethylamine, preferably triethylamine. Suitable solvents include toluene, or methylene chloride, preferably toluene.
Konačni produkti formule XI također se mogu saponificirati do slobodne kiseline upotrebom baze kao što je natrij-hidroksid u protonskom otapalu kao npr. etanol, metanol ili voda ili smjesa kao npr. voda i etanol, voda i toluen, ili voda i THF. Poželjan sustav otapala je voda i toluen. Reakcija se provodi u periodu od 30 minuta do 24 sata, poželjno oko 2 sata. The final products of formula XI can also be saponified to the free acid using a base such as sodium hydroxide in a protic solvent such as ethanol, methanol or water or a mixture such as water and ethanol, water and toluene, or water and THF. The preferred solvent system is water and toluene. The reaction is carried out over a period of 30 minutes to 24 hours, preferably around 2 hours.
Spojevi formule XI koji su bazični po svojoj prirodi, sposobni su za formiranje velikog broja različitih soli s raznim anorganskim i organskim kiselinama. Iako takve soli moraju biti farmaceutski prihvatljive za primjenu na životinjama, često je poželjno u praksi najprije izolirati spoj formule XI iz reakcijske smjese kao farmaceutski neprihvatljivu sol i zatim je jednostavno pretvoriti u spoj koji je slobodna baza obradom s alkalnim reagensom, i kasnije pretvoriti slobodnu bazu u farmaceutski prihvatljivu adicijsku kiselu sol. Adicijske kisele soli bazičnih spojeva iz ovog izuma lako se pripremaju obrađivanjem bazičnog spoja sa stvarnom ekvivalentnom količinom odabrane mineralne ili organske kiseline u vodenom mediju otapala ili u prikladnom organskom otapalu kao što je metanol ili etanol. Nakon pažljivog otparavanja otapala, dobije se željena kruta sol. Compounds of formula XI, which are basic in nature, are capable of forming a large number of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for use in animals, it is often desirable in practice to first isolate the compound of formula XI from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert it to the free base compound by treatment with an alkaline reagent, and later convert the free base into a pharmaceutically acceptable acid addition salt. Acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with an actual equivalent amount of a selected mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol. After careful evaporation of the solvent, the desired solid salt is obtained.
Kiseline koje se upotrebljavaju za pripravu farmaceutski prihvatljivih adicijskih kiselih soli od bazičnih spojeva iz ovog izuma su one koje formiraju netoksične adicijske kisele soli, tj. soli koje sadrže farmakološki prihvatljive anione, kao što su hidroklorid, hidrobromid, hidrojodid, nitrat, sulfat ili bisulfat, fosfat ili kiseli fosfat, acetat, laktat, citrat ili kiseli citrat, tartarat ili bitartarat, sukcinat, maleat, fumarat, glukonat, saharat, benzoat, metansulfonat i pamoat [tj. 1,1’-metilen-bis-(2-hidroksi-3-naftoat)] soli. The acids used for the preparation of pharmaceutically acceptable acid addition salts from the basic compounds of this invention are those that form non-toxic acid addition salts, i.e. salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate and pamoate [i.e. 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)] salts.
Oni spojevi formule XI koji su također kiseli po prirodi, sposobni su za formiranje bazičnih soli s raznim farmakološki prihvatljivim kationima. Primjeri takvih soli uključuju soli alkalijskih ili zemnoalkalijskih metala i naročito, natrijeve i kalijeve soli. Ove soli se sve pripremaju konvencionalnim tehnikama. Kemijske baze koje se koriste kao reagensi za pripravu farmaceutski prihvatljivih bazičnih soli iz ovog izuma su one koje formiraju netoksične bazične soli s ovdje opisanim kiselim spojevima formule XI. Te netoksične bazične soli uključuju one izvedene od takvih farmakološki prihvatljivih kationa kao što su natrij, kalij, kalcij i magnezij, itd. Te soli se lako mogu dobiti obrađivanjem odgovarajućih kiselih spojeva vodenom otopinom koja sadrži željene farmakološki prihvatljive katione, i zatim uparavanjem nastale otopine do suhoće, poželjno pod sniženim tlakom. Alternativno, one se također mogu dobiti spajanjem otopina kiselih spojeva u nižem alkanolu i alkoksida željenog alkalijskog metala, i zatim uparavanjem nastale otopine do suhoće na isti način kao prije. U svakom slučaju, poželjno se upotrebljavaju stehiometrijske količine reagenata da bi se osigurala potpunost reakcije i maksimalni prinosi produkta. Those compounds of formula XI which are also acidic in nature are capable of forming basic salts with various pharmacologically acceptable cations. Examples of such salts include salts of alkali or alkaline earth metals and, in particular, sodium and potassium salts. These salts are all prepared using conventional techniques. Chemical bases used as reagents for the preparation of pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the acid compounds of formula XI described herein. These non-toxic basic salts include those derived from such pharmacologically acceptable cations as sodium, potassium, calcium and magnesium, etc. These salts can be readily obtained by treating the corresponding acid compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they can also be obtained by combining solutions of acidic compounds in a lower alkanol and alkoxide of the desired alkali metal, and then evaporating the resulting solution to dryness in the same manner as before. In any case, stoichiometric amounts of reagents are preferably used to ensure completeness of the reaction and maximum product yields.
Sposobnost spojeva formule XI ili njihovih farmaceutski prihvatljivih soli (dalje također naznačene kao aktivni spojevi) za inhibiciju matriks metaloproteinaza ili produkciju tumor nekrotizirajućeg faktora (TNF) i, prema tome, za pokazivanje njihove djelotvornosti u liječenju bolesti karakteriziranih matriks metaloproteinazom ili produkcijom tumor nekrotizirajućeg faktora se može odrediti prema in vitro analitičkim testovima dobro poznatim stručnjacima. Jedan primjer ispitivanja koji potvrđuje da su konačni produkti proizvedeni metodama iz izuma je test inhibicije humane kolagenaze. The ability of compounds of formula XI or their pharmaceutically acceptable salts (hereinafter also referred to as active compounds) to inhibit matrix metalloproteinases or tumor necrosis factor (TNF) production and, therefore, to demonstrate their effectiveness in the treatment of diseases characterized by matrix metalloproteinase or tumor necrosis factor production is can be determined according to in vitro analytical tests well known to those skilled in the art. One example of a test that confirms that the final products are produced by the methods of the invention is the human collagenase inhibition test.
BIOLOŠKI POKUS BIOLOGICAL EXPERIMENT
Inhibicija humane kolagenaze (MMP-1) Inhibition of human collagenase (MMP-1)
Humana rekombinirana kolagenaza aktivira se tripsinom upotrebom slijedećeg omjera: 10 µg tripsina na 100 µg kolagenaze. Tripsin i kolagenaza inkubiraju se na sobnoj temperaturi 10 minuta zatim se doda pet puta veći suvišak (50 µg/10 µg tripsina) sojinog inhibitora tripsina. Human recombinant collagenase is activated by trypsin using the following ratio: 10 µg of trypsin per 100 µg of collagenase. Trypsin and collagenase are incubated at room temperature for 10 minutes, then a fivefold excess (50 µg/10 µg trypsin) of soy trypsin inhibitor is added.
10 mM otopine s inhibitorima je već pripremljeno u dimetil-sulfoksidu i zatim se razrijedi prema slijedećoj shemi: 10 mM inhibitor solution is already prepared in dimethyl sulfoxide and then diluted according to the following scheme:
10 mM → 120 µM → 12 µM → 1,2 µM → 0,12 µM 10 mM → 120 µM → 12 µM → 1.2 µM → 0.12 µM
Dvadeset i pet mikrolitara svake koncentracije se zatim doda trostruko u odgovarajući otvor microfluor ploče sa 96 otvora. Konačna koncentracija inhibitora biti će razrjeđenje 1:4 nakon dodatka enzima i supstrata. Pozitivne kontrolne probe (enzim, bez inhibitora) se postave u otvorima D1-D6 i slijepe probe (bez enzima, bez inhibitora) se postave u otvorima D7-D12. Twenty-five microliters of each concentration is then added in triplicate to the appropriate well of a 96-well microfluor plate. The final inhibitor concentration will be a 1:4 dilution after addition of enzyme and substrate. Positive controls (enzyme, no inhibitor) are placed in slots D1-D6 and blanks (no enzyme, no inhibitor) are placed in slots D7-D12.
Kolagenaza se razrijedi do 400 ng/ml i zatim se po 25 µl doda u odgovarajuće otvore microfluor ploče. Konačna koncentracija kolagenaze u testu je 100 ng/ml. Collagenase is diluted to 400 ng/ml and then 25 µl is added to the corresponding openings of the microfluor plate. The final concentration of collagenase in the test is 100 ng/ml.
Supstrat (DNP-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMA)-NH2) se načini kao 5 mM otopina u dimetil-sulfoksidu i zatim razrijedi do 20 mM u test-puferu. Test započinje dodatkom 50 μl supstrata po otvoru microfluor ploče da se dobije konačna koncentracija od 10 µM. The substrate (DNP-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMA)-NH2) was prepared as a 5 mM solution in dimethyl sulfoxide and then diluted to 20 mM in assay buffer. The test starts with the addition of 50 μl of substrate per microfluor plate opening to obtain a final concentration of 10 μM.
Očitanja fluorescencije (ekscitacija 360 nm, emisija 460 nm) se uzimaju u vremenu 0 i zatim u intervalima od 20 minuta. Test se provodi na sobnoj temperaturi sa tipičnim vremenom ispitivanja od 3 sata. Fluorescence readings (excitation 360 nm, emission 460 nm) are taken at time 0 and then at 20 minute intervals. The test is performed at room temperature with a typical test time of 3 hours.
Omjer fluorescencije prema vremenu se zatim prikazuje grafički i za slijepe probe i za uzorke koji sadrže kolagenazu (podacima iz trostrukih određivanja se izračuna srednja vrijednost). Točka vremena u kojoj se dobiva dobar signal (početni signal) i koja je na linearnom dijelu krivulje (obično oko 120 minuta) odabire se za određivanje IC50 vrijednosti. Nulto vrijeme se upotrebljava kao početni signal za svaki spoj u svakoj koncentraciji i te vrijednosti se oduzimaju od podataka za vrijeme 120 minuta. Podaci se unose u dijagram kao koncentracija inhibitora prema %-tku kontrolne probe (fluorescencija inhibitora podijeljena sa fluorescencijom same kolagenaze × 100). IC50 vrijednosti se određuju iz koncentracije inhibitora koja daje signal kao 50 % kontrolne probe. The ratio of fluorescence versus time is then plotted graphically for both blanks and collagenase-containing samples (data from triplicate determinations are averaged). The time point at which a good signal is obtained (initial signal) and which is on the linear part of the curve (usually around 120 minutes) is chosen to determine the IC50 value. Zero time is used as the initial signal for each compound at each concentration and these values are subtracted from the data for 120 minutes. The data are entered in the diagram as the concentration of the inhibitor in % of the control sample (fluorescence of the inhibitor divided by the fluorescence of the collagenase itself × 100). IC50 values are determined from the inhibitor concentration that gives a signal as 50% of the control sample.
Ako IC50 vrijednosti ispadnu <0,03 µM, onda se inhibitori ispituju u koncentracijama od 0,3 µM, 0,03 µM, 0,03 µM i 0,003 µM. If the IC50 values are <0.03 µM, then the inhibitors are tested at concentrations of 0.3 µM, 0.03 µM, 0.03 µM and 0.003 µM.
Slijedeći primjeri pokazuju pripravu spojeva iz ovog izuma. Točke tališta nisu ispravljene. NMR podaci su izraženi u dijelovima na milijun (δ) i odnose se na deuterijev početni signal iz otapala uzorka (deuteriokloroform ako nije drugačije naznačeno). Komercijalni reagensi su upotrijebljeni bez daljnjeg pročišćavanja. THF se odnosi na tetrahidrofuran. DMF se odnosi na N,N-dimetilformamid. Kromatografija se odnosi na kromatografiju na stupcu izvođenu upotrebom 32-63 mm silika-gela i izvedenu u uvjetima pritiska dušika (flash kromatografija). Sobna ili ambijentalna temperatura znači 20-25 °C. Sve bezvodne reakcije su provedene u atmosferi dušika zbog prikladnosti i da se povećaju prinosi. Koncentriranje pri sniženom tlaku znači da je upotrijebljen rotirajući evaporator. The following examples demonstrate the preparation of the compounds of this invention. Melting points are not corrected. NMR data are expressed in parts per million (δ) and refer to the initial deuterium signal from the sample solvent (deuteriochloroform unless otherwise noted). Commercial reagents were used without further purification. THF refers to tetrahydrofuran. DMF refers to N,N-dimethylformamide. Chromatography refers to column chromatography performed using 32-63 mm silica gel and performed under nitrogen pressure conditions (flash chromatography). Room or ambient temperature means 20-25 °C. All anhydrous reactions were carried out under a nitrogen atmosphere for convenience and to increase yields. Concentration at reduced pressure means that a rotary evaporator is used.
Primjer 1 Example 1
4-fluorofenil ester 4-(4-fluorofenoksi)benzensulfonske kiseline 4-fluorophenyl ester of 4-(4-fluorophenoxy)benzenesulfonic acid
Otopina 14,68 g (0,131 mol, 2,0 ekvivalenta) kalij-tert-butoksida u 27 ml suhog N-metilpirolidinona obrađuje se s otopinom 15,39 g (0,137 mol, 2,1 ekvivalent) 4-fluorofenola u 27 ml suhog N-metilpirolidinona pri sobnoj temperaturi, što uzrokuje blago oslobađanje topline do 45 °C. Otopina 13,81 g (0,065 mol) 4-klorbenzensulfonil klorida u 27 ml suhog N-metilpirolidinona polako se doda tamnoj reakcijskoj smjesi što uzrokuje blago oslobađanje topline do 44 °C. Rezultirajuća smjesa se miješa pri sobnoj temperaturi 1 sat i zatim pri 130 °C 11 sati. Ohlađena reakcijska smjesa obrađuje se sa 162 ml vode, zasije s tragovima 4-fluorofenil estera 4-(4-fluorofenoksi)benzensulfonske kiseline, i granulira pri sobnoj temperaturi preko noći. Rezultirajuća krutina se filtrira dajući 20,24 g (85 %) 4-fluorofenil estera 4-(4-fluorofenoksi)benzensulfonske kiseline. A solution of 14.68 g (0.131 mol, 2.0 equivalents) of potassium tert-butoxide in 27 ml of dry N-methylpyrrolidinone is treated with a solution of 15.39 g (0.137 mol, 2.1 equivalents) of 4-fluorophenol in 27 ml of dry of N-methylpyrrolidinone at room temperature, which causes a slight release of heat up to 45 °C. A solution of 13.81 g (0.065 mol) of 4-chlorobenzenesulfonyl chloride in 27 ml of dry N-methylpyrrolidinone was slowly added to the dark reaction mixture causing a slight release of heat up to 44 °C. The resulting mixture was stirred at room temperature for 1 hour and then at 130 °C for 11 hours. The cooled reaction mixture is treated with 162 ml of water, seeded with traces of 4-(4-fluorophenoxy)benzenesulfonic acid 4-fluorophenyl ester, and granulated at room temperature overnight. The resulting solid was filtered to give 20.24 g (85%) of 4-(4-fluorophenoxy)benzenesulfonic acid 4-fluorophenyl ester.
1H NMR (CDCl3) δ 7,74 (dd, J=7,0, 2,0 Hz, 2H); 7,14-6,97 (m, 10H). Talište 78-83 °C. 1 H NMR (CDCl 3 ) δ 7.74 (dd, J=7.0, 2.0 Hz, 2H); 7.14-6.97 (m, 10H). Melting point 78-83 °C.
Primjer 2 Example 2
4-(4-fluorofenoksi)benzensulfonska kiselina, natrijeva sol 4-(4-fluorophenoxy)benzenesulfonic acid, sodium salt
Žitkoj kaši koja se sastoji od 47,43 g (0,131 mol) 4-fluorofenil estera 4-(4-fluorofenoksi)benzensulfonske kiseline u 475 ml etanola doda se 13,09 g (0,327 mol, 2,5 ekvivalenta) peleta natrij-hidroksida. Ova smjesa se zagrijava pod refluksom 3 sata i miješa preko noći pri sobnoj temperaturi. Rezultirajuća krutina se filtrira dajući 37,16 g (98 %) natrijeve soli 4-(4-fluorofenoksi)benzensulfonske kiseline. To a slurry consisting of 47.43 g (0.131 mol) of 4-fluorophenyl ester of 4-(4-fluorophenoxy)benzenesulfonic acid in 475 ml of ethanol is added 13.09 g (0.327 mol, 2.5 equivalents) of sodium hydroxide pellets. . This mixture is heated under reflux for 3 hours and stirred overnight at room temperature. The resulting solid was filtered to give 37.16 g (98%) of the sodium salt of 4-(4-fluorophenoxy)benzenesulfonic acid.
1H NMR (CD3OD) δ 7,73-7,78 (m, 2H); 7,05-7,13 (m, 2H); 6,99-7,05 (m, 2H); 6,90-6,95 (m, 2H). 1H NMR (CD3OD) δ 7.73-7.78 (m, 2H); 7.05-7.13 (m, 2H); 6.99-7.05 (m, 2H); 6.90-6.95 (m, 2H).
Primjer 3 Example 3
4-(4-fluorofenoksi)benzensulfonil klorid 4-(4-fluorophenoxy)benzenesulfonyl chloride
Žitkoj kaši koja se sastoji od 15,0 g (0,052 mol) natrijeve soli 4-(4-fluorofenoksi)benzensulfonske kiseline u 150 ml suhog toluena doda se 11,3 ml (0,155 mol, 3 ekvivalenta) tionil-klorida i 0,04 ml (0,5 mmol, 0,01 ekvivalent) dimetilformamida. Rezultirajuća smjesa se miješa pri sobnoj temperaturi 48 sati, filtrira kroz dijatomejsku zemlju, i ukoncentrira pod sniženim tlakom do 40 ml. Ova otopina se upotrijebi bez daljnjeg pročišćavanja za pripravu benzilnog estera 1-[4-(4-fluorofenoksi)benzensulfonilamino] ciklopentankarboksilne kiseline. 11.3 ml (0.155 mol, 3 equivalents) of thionyl chloride and 0.04 ml (0.5 mmol, 0.01 equivalent) of dimethylformamide. The resulting mixture is stirred at room temperature for 48 hours, filtered through diatomaceous earth, and concentrated under reduced pressure to 40 ml. This solution was used without further purification for the preparation of 1-[4-(4-fluorophenoxy)benzenesulfonylamino]cyclopentanecarboxylic acid benzyl ester.
Porcija od 5,0 ml ove otopine se ukoncentrira do 1,77 g 4-(4-fluorofenoksi)benzensulfonil klorida kao ulja, što odgovara 96 %-tnom prinosu. A 5.0 ml portion of this solution was concentrated to 1.77 g of 4-(4-fluorophenoxy)benzenesulfonyl chloride as an oil, corresponding to a 96% yield.
1H NMR (CDCl3) δ 7,92-7,97 (m, 2H); 7,01-7,13 (m, 6H). Porcija slično pripremljenog ulja se kristalizira iz heksana, talište 80 °C. 1 H NMR (CDCl 3 ) δ 7.92-7.97 (m, 2H); 7.01-7.13 (m, 6H). A portion of similarly prepared oil is crystallized from hexane, melting point 80 °C.
Priprava 1 Preparation 1
3-[[4-(4-fluorofenoksi)benzensulfonil]-(1-hidroksikarbamoil-ciklopentil)-amino]propionska kiselina 3-[[4-(4-fluorophenoxy)benzenesulfonyl]-(1-hydroxycarbamoyl-cyclopentyl)-amino]propionic acid
A) Benzil ester 1-[4-(4-fluorofenoksi)benzensulfonilamino]ciklopentankarboksilne kiseline A) Benzyl ester of 1-[4-(4-fluorophenoxy)benzenesulfonylamino]cyclopentanecarboxylic acid
Smjesi 12,41 g (0,032 mol) benzilnog estera 1-aminociklopentankarboksilne kiseline, kao soli toluen-4-sulfonske kiseline, (može se pripremiti prema metodama kao što su one opisane u US patentu br. 4.745.124) i 10,0 g (0,035 mol, 1.1 ekvivalent) 4-(4-fluorofenoksi)benzensulfonil klorida (pripremljenog prema pripravi 3) u 113 ml toluena doda se 11,0 ml (0,079 mol, 2,5 ekvivalenta) trietilamina. Rezultirajuća smjesa se miješa pri sobnoj temperaturi preko noći, ispere s 2N kloridnom kiselinom (2 × 100 ml) i slanom vodom (100 ml), osuši iznad natrij-sulfata, i ukoncentrira do 30 ml. Doda se heksan, 149 ml, kap po kap tijekom 3 sata pri čemu nastaje kruti precipitat koji se granulira pri 0 °C tijekom 1 sata i filtrira dajući 12,59 g (85 %) benzilnog estera 1-[4-(4-fluorofenoksi)benzensulfonilamino]ciklopentan-karboksilne kiseline. Mixtures of 12.41 g (0.032 mol) of 1-aminocyclopentanecarboxylic acid benzyl ester, as the toluene-4-sulfonic acid salt, (can be prepared by methods such as those described in US Pat. No. 4,745,124) and 10.0 g (0.035 mol, 1.1 equivalent) of 4-(4-fluorophenoxy)benzenesulfonyl chloride (prepared according to preparation 3) in 113 ml of toluene is added 11.0 ml (0.079 mol, 2.5 equivalent) of triethylamine. The resulting mixture was stirred at room temperature overnight, washed with 2N hydrochloric acid (2 x 100 ml) and brine (100 ml), dried over sodium sulfate, and concentrated to 30 ml. Hexane, 149 ml, was added dropwise over 3 hours to form a solid precipitate which was granulated at 0 °C over 1 hour and filtered to give 12.59 g (85%) of 1-[4-(4-fluorophenoxy) benzyl ester. )benzenesulfonylamino]cyclopentane-carboxylic acids.
1H NMR (CDCl3) δ 7,78-7,82 (m, 2H); 7,30-7,39 (m, 5H); 7,06-7,12 (m, 2H); 6,99-7,04 (m, 2H); 6,93-6,97 (m, 2H); 5,15 (s, 1H); 5,02 (s, 2H); 2,04-2,13 (m, 2H); 1,92-1,98 (m, 2H); 1,62-1,69 (m, 4H). 1 H NMR (CDCl 3 ) δ 7.78-7.82 (m, 2H); 7.30-7.39 (m, 5H); 7.06-7.12 (m, 2H); 6.99-7.04 (m, 2H); 6.93-6.97 (m, 2H); 5.15 (s, 1H); 5.02 (s, 2H); 2.04-2.13 (m, 2H); 1.92-1.98 (m, 2H); 1.62-1.69 (m, 4H).
4,0 g uzorka se granulira u smjesi 4 ml etil acetata i 40 ml heksana preko noći dajući 3,72 g (93 % regeneracija) benzilnog estera 1-[4-(4-fluorofenoksi)benzensulfonilamino]ciklopentan-karboksilne kiseline kao svijetlo putenaste krutine, talište 97,0-97,5 °C. 4.0 g of the sample was granulated in a mixture of 4 ml of ethyl acetate and 40 ml of hexane overnight to give 3.72 g (93 % recovery) of 1-[4-(4-fluorophenoxy)benzenesulfonylamino]cyclopentanecarboxylic acid benzyl ester as a pale yellow solids, melting point 97.0-97.5 °C.
B) Benzil ester 1-{(2-etoksikarbonilvinil)-[4-(4-fluorofenoksi)benzensulfonil]amino}-ciklopentan-karboksilne kiseline B) Benzyl ester of 1-{(2-ethoxycarbonylvinyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}-cyclopentane-carboxylic acid
Otopina 25,0 g (53,2 mmol) benzilnog estera 1-[4-(4-fluorofenoksi)benzensulfonilamino]ciklopentan-karboksilne kiseline i 10,8 ml (106 mmol, 2 ekvivalenta) etil propiolata u 200 ml suhog tetrahidrofurana pri 1 °C obrađuje se s 53,2 ml (53,2 mmol, 1 ekvivalent) otopine tetrabutilamonij-fluorida u tetrahidrofuranu (1M) tijekom 45 minuta. Rezultirajuća otopina se ostavi da se polako ugrije do sobne temperature i miješa preko noći. Tetrahidrofuran se ukloni pomoću toluena pri sniženom tlaku, i otopina u toluenu se ispere vodom i slanom vodom, razrijedi do 600 ml s toluenom, miješa sa 90 g silika-gela 3 sata, filtrira i ukoncentrira do 25,14 g (83 %) benzilnog estera 1-{(2-etoksikarbonilvinil)-[4-(4-fluorofenoksi) benzensulfonil]amino}-ciklopentan-karboksilne kiseline kao narančastog ulja. 1H NMR (CDCl3) je pokazao omjer 1,5:1 trans/cis oblika. A solution of 25.0 g (53.2 mmol) of 1-[4-(4-fluorophenoxy)benzenesulfonylamino]cyclopentanecarboxylic acid benzyl ester and 10.8 ml (106 mmol, 2 equivalents) of ethyl propiolate in 200 ml of dry tetrahydrofuran at 1 °C is treated with 53.2 ml (53.2 mmol, 1 equivalent) of a solution of tetrabutylammonium fluoride in tetrahydrofuran (1M) for 45 minutes. The resulting solution is allowed to slowly warm to room temperature and stirred overnight. Tetrahydrofuran is removed using toluene under reduced pressure, and the toluene solution is washed with water and brine, diluted to 600 ml with toluene, mixed with 90 g of silica gel for 3 hours, filtered and concentrated to 25.14 g (83%) of benzyl 1-{(2-ethoxycarbonylvinyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}-cyclopentanecarboxylic acid ester as an orange oil. 1H NMR (CDCl3) showed a 1.5:1 ratio of trans/cis forms.
Trans δ 7,74-7,78 (m, 2H); 7,72 (d, J=14 Hz, 1H); 7,26-7,36 (m, 5H); 6,96-7,12 (m, 4H); 6,78-6,84 (m, 2H); 5,44 (d, J=14 Hz, 1H); 5,11 (s, 2H); 4,12 (q, J=7,1 Hz, 2H); 2,08-2,43 (m, 4H); 1,63-1,80 (m, 4H); 1,24 (t, J=7,1 Hz, 3H). Trans δ 7.74-7.78 (m, 2H); 7.72 (d, J=14 Hz, 1H); 7.26-7.36 (m, 5H); 6.96-7.12 (m, 4H); 6.78-6.84 (m, 2H); 5.44 (d, J=14 Hz, 1H); 5.11 (s, 2H); 4.12 (q, J=7.1 Hz, 2H); 2.08-2.43 (m, 4H); 1.63-1.80 (m, 4H); 1.24 (t, J=7.1 Hz, 3H).
Cis δ 7,68-7,72 (m, 2H); 7,26-7,36 (m, 5H); 6,96-7,12 (m, 4H); 6,86-6,91 (m, 2H); 6,47 (d, J=8,1 Hz, 1H); 5,90 (d, J=8,1 Hz, 1H); 5,11 (s, 2H); 3,93 (q, J=7,2 Hz, 2H); 2,08-2,43 (m, 4H); 1,63-1,80 (m, 4H); 1,17 (t, J=7,2 Hz, 3H). Cis δ 7.68-7.72 (m, 2H); 7.26-7.36 (m, 5H); 6.96-7.12 (m, 4H); 6.86-6.91 (m, 2H); 6.47 (d, J=8.1 Hz, 1H); 5.90 (d, J=8.1 Hz, 1H); 5.11 (s, 2H); 3.93 (q, J=7.2 Hz, 2H); 2.08-2.43 (m, 4H); 1.63-1.80 (m, 4H); 1.17 (t, J=7.2 Hz, 3H).
C) {(2-etoksikarboniletil)-[4-(4-fluorofenoksi)benzensulfonil]amino}-ciklopentankarboksilna kiselina C) {(2-ethoxycarbonylethyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}-cyclopentanecarboxylic acid
Otopina 2,50 g (4,4 mmol) benzilnog estera 1-{(2-etoksikarbonilvinil)-[4-(4-fluorofenoksi)benzensulfonil]-amino}ciklopentankarboksilne kiseline u 25 ml etanola obrađuje se sa 2,5 g 50 % vlažnog 10 % katalizatora paladija na ugljiku i mućka pod 3,654221365 bara (53 psi) vodika 21 sat. Katalizator se ukloni filtracijom i ispere etanolom (4 × 25 ml). Filtrat i otopine od ispiranja se sjedine i ukoncentriraju pod vakuumom do 1,74 g (82 %) sirove 1-{(2-etoksikarboniletil)-[4-(4-fluorofenoksi)benzensulfonil]amino}ciklopentankarboksilne kiseline kao viskoznog ulja. A solution of 2.50 g (4.4 mmol) of 1-{(2-ethoxycarbonylvinyl)-[4-(4-fluorophenoxy)benzenesulfonyl]-amino}cyclopentanecarboxylic acid benzyl ester in 25 ml of ethanol is treated with 2.5 g of 50 % wet 10% palladium on carbon catalyst and shake under 3.654221365 bar (53 psi) hydrogen for 21 hrs. The catalyst was removed by filtration and washed with ethanol (4 x 25 ml). The filtrate and washings were combined and concentrated in vacuo to 1.74 g (82%) of crude 1-{(2-ethoxycarbonylethyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}cyclopentanecarboxylic acid as a viscous oil.
1H NMR (CDCl3) δ 7,78-7,82 (m, 2H); 6,94-7,09 (m, 6H); 4,09 (q, J=7,2 Hz, 2H); 3,56-3,60 (m, 2H); 2,75-2,79 (m, 2H); 2,33-2,39 (m, 2H); 1,93-2,03 (m, 2H); 1,69-1,76 (m, 2H); 1,56-1,63 (m, 2H); 1,22 (t, J=7,2 Hz, 3H). 1 H NMR (CDCl 3 ) δ 7.78-7.82 (m, 2H); 6.94-7.09 (m, 6H); 4.09 (q, J=7.2 Hz, 2H); 3.56-3.60 (m, 2H); 2.75-2.79 (m, 2H); 2.33-2.39 (m, 2H); 1.93-2.03 (m, 2H); 1.69-1.76 (m, 2H); 1.56-1.63 (m, 2H); 1.22 (t, J=7.2 Hz, 3H).
D) {(2-etoksikarboniletil)-[4-(4-fluorofenoksi)benzensulfonil]amino}-ciklopentankarboksilna kiselina, D) {(2-ethoxycarbonylethyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}-cyclopentanecarboxylic acid,
dicikloheksilaminijeva sol dicyclohexylamine salt
Otopina 3,10 g (6,5 mmol) sirove 1-{(2-etoksikarboniletil)-[4-(4-fluorofenoksi)benzensulfonil]amino}-ciklopentankarboksilne kiseline u 30 ml etanola obrađuje se s 1,28 ml (6,5 mmol, 1 ekvivalent) dicikloheksilamina pri sobnoj temperaturi pri čemu nastaje krutina unutar 5 minuta. Ova smjesa se miješa pri sobnoj temperaturi preko noći i zatim pri 0 °C tijekom 5 sati. Bijela krutina se izolira filtracijom, ispere sa 10 ml hladnog etanola, i osuši na zraku pri čemu nastaje 2,89 g (67 %) dicikloheksilaminijeve soli 1-{(2-etoksikarboniletil)-[4-(4-fluorofenoksi)benzensulfonil]amino}ciklopentankarboksilne kiseline. A solution of 3.10 g (6.5 mmol) of crude 1-{(2-ethoxycarbonylethyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}-cyclopentanecarboxylic acid in 30 ml of ethanol is treated with 1.28 ml (6, 5 mmol, 1 equivalent) of dicyclohexylamine at room temperature where a solid forms within 5 minutes. This mixture was stirred at room temperature overnight and then at 0 °C for 5 hours. The white solid is isolated by filtration, washed with 10 ml of cold ethanol, and air-dried to give 2.89 g (67%) of the dicyclohexylamine salt of 1-{(2-ethoxycarbonylethyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino }cyclopentanecarboxylic acids.
1H NMR (CDCl3) δ 7,86-7,91 (m, 2H); 6,99-7,09 (m, 4H); 6,90-6,94 (m, 2H); 5,3 (br s, 2H); 4,07 (q, J=7,1 Hz, 2H); 3,54-3,59 (m, 2H); 2,88-2,95 (m, 4H); 2,31-2,38 (m, 2H); 1,95-2,22 (m, 6H); 1,68-1,77 (m, 6H); 1,53-1,60 (m, 4H); 1,40-1,50 (m, 4H); 1,21 (t, J=7,1 Hz, 3H); 1,14-1,22 (m, 6H). Talište 164,5-165,9 °C. 1H NMR (CDCl 3 ) δ 7.86-7.91 (m, 2H); 6.99-7.09 (m, 4H); 6.90-6.94 (m, 2H); 5.3 (no. s, 2H); 4.07 (q, J=7.1 Hz, 2H); 3.54-3.59 (m, 2H); 2.88-2.95 (m, 4H); 2.31-2.38 (m, 2H); 1.95-2.22 (m, 6H); 1.68-1.77 (m, 6H); 1.53-1.60 (m, 4H); 1.40-1.50 (m, 4H); 1.21 (t, J=7.1 Hz, 3H); 1.14-1.22 (m, 6H). Melting point 164.5-165.9 °C.
E) {(2-etoksikarboniletil)-[4-(4-fluorofenoksi)benzensulfonil]amino}-ciklopentankarboksilna kiselina E) {(2-ethoxycarbonylethyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}-cyclopentanecarboxylic acid
Otopina 3,0 g (4,5 mmol) dicikloheksilaminijeve soli 1-{(2-etoksikarboniletil)-[4-(4-fluorofenoksi)benzen-sulfonil]amino}ciklopentankarboksilne kiseline u 30 ml diklormetana obrađuje se sa 30 ml 2N kloridne kiseline pri sobnoj temperaturi što uzrokuje neposredno taloženje krutine. Ova smjesa se miješa pri sobnoj temperaturi 3 sata. Krutina se filtrira, vodena faza se ekstrahira sa diklormetanom, i sjedinjene organske faze se isperu vodom, osuše iznad natrij-sulfata, i ukoncentriraju u vakuumu do 2,2 g (100 %) 1-{(2-etoksikarboniletil)-[4-(4-fluorofenoksi)benzensulfonil]amino}ciklopentankarboksilne kiseline kao bistrog ulja. A solution of 3.0 g (4.5 mmol) of the dicyclohexylaminium salt of 1-{(2-ethoxycarbonylethyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}cyclopentanecarboxylic acid in 30 ml of dichloromethane is treated with 30 ml of 2N hydrochloric acid. at room temperature which causes immediate precipitation of the solid. This mixture was stirred at room temperature for 3 hours. The solid is filtered, the aqueous phase is extracted with dichloromethane, and the combined organic phases are washed with water, dried over sodium sulfate, and concentrated in vacuo to 2.2 g (100%) of 1-{(2-ethoxycarbonylethyl)-[4- (4-fluorophenoxy)benzenesulfonyl]amino}cyclopentanecarboxylic acid as a clear oil.
1H NMR (DMSO-d6) δ 12,68 (bs, 1H); 7,76-7,80 (m, 2H); 7,25-7,31 (m, 2H); 7,16-7,21 (m, 2H); 7,03-7,08 (m, 2H); 4,01 (q, J=7,1 Hz, 2H); 3,48-3,54 (m, 2H); 2,64-2,70 (m, 2H); 2,13-2,21 (m, 2H); 1,90-1,98 (m, 2H); 1,52-1,59 (m, 4H); 1,14 (t, J=7,1 Hz, 3H). 1H NMR (DMSO-d6) δ 12.68 (bs, 1H); 7.76-7.80 (m, 2H); 7.25-7.31 (m, 2H); 7.16-7.21 (m, 2H); 7.03-7.08 (m, 2H); 4.01 (q, J=7.1 Hz, 2H); 3.48-3.54 (m, 2H); 2.64-2.70 (m, 2H); 2.13-2.21 (m, 2H); 1.90-1.98 (m, 2H); 1.52-1.59 (m, 4H); 1.14 (t, J=7.1 Hz, 3H).
F) Etil ester 3-{(1-klorokarbonilciklopentil)-[4-(4-fluorofenoksi)benzensulfonil]amino}propionske kiseline F) Ethyl ester of 3-{(1-chlorocarbonylcyclopentyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}propionic acid
Otopina 7,26 g (15,1 mmol) 1-{(2-etoksikarboniletil)-[4-(4-fluorofenoksi)benzensulfonil]amino} ciklopentan-karboksilne kiseline u 73 ml diklormetana obrađuje se sa 1,4 ml (17 mmol, 1,1 ekvivalent) oksalil-klorida i 0,02 ml (0,3 mmol, 0,02 ekvivalenta) dimetilformamida pri sobnoj temperaturi, uzrokujući nešto pjenjenja, i miješa preko noći. Rezultirajuća otopina etilnog estera 3-{(1-klorokarbonilciklopentil)-[4-(4-fluorofenoksi)-benzensulfonil]amino}propionske kiseline upotrijebi se za pripravu etilnog estera 3-[[4-(4-fluorofenoksi)-benzensulfonil]-(1-hidroksikarbamoilciklopentil)amino] propionske kiseline bez izolacije. A solution of 7.26 g (15.1 mmol) of 1-{(2-ethoxycarbonylethyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino} cyclopentanecarboxylic acid in 73 ml of dichloromethane is treated with 1.4 ml (17 mmol , 1.1 equiv) of oxalyl chloride and 0.02 ml (0.3 mmol, 0.02 equiv) of dimethylformamide at room temperature, causing some foaming, and stirred overnight. The resulting solution of 3-{(1-chlorocarbonylcyclopentyl)-[4-(4-fluorophenoxy)-benzenesulfonyl]amino}propionic acid ethyl ester was used to prepare 3-[[4-(4-fluorophenoxy)-benzenesulfonyl]-( 1-Hydroxycarbamoylcyclopentyl)amino] propionic acid without isolation.
Slično pripremljena otopina etilnog estera 3-{(1-klorokarbonilciklopentil)-[4-(4-fluorofenoksi)benzen-sulfonil]amino}propionske kiseline ukoncentrira se u vakuumu do ulja. A similarly prepared solution of 3-{(1-chlorocarbonylcyclopentyl)-[4-(4-fluorophenoxy)benzenesulfonyl]amino}propionic acid ethyl ester is concentrated in vacuo to an oil.
1H NMR (CDCl3) δ 7,84-7,87 (m, 2H); 6,97-7,12 (m, 6H); 4,10 (q, J=7,2 Hz, 2H); 3,55-3,59 (m, 2H); 2,68-2,72 (m, 2H); 2,47-2,53 (m, 2H); 1,95-2,02 (m, 2H); 1,71-1,76 (m, 4H); 1,24 (t, J=7,2 Hz, 3H). 1H NMR (CDCl 3 ) δ 7.84-7.87 (m, 2H); 6.97-7.12 (m, 6H); 4.10 (q, J=7.2 Hz, 2H); 3.55-3.59 (m, 2H); 2.68-2.72 (m, 2H); 2.47-2.53 (m, 2H); 1.95-2.02 (m, 2H); 1.71-1.76 (m, 4H); 1.24 (t, J=7.2 Hz, 3H).
G) Etil ester 3-[[4-(4-fluorofenoksi)benzensulfonil]-(1-hidroksikarbamoilciklopentil)amino]propionske kiseline G) Ethyl ester of 3-[[4-(4-fluorophenoxy)benzenesulfonyl]-(1-hydroxycarbamoylcyclopentyl)amino]propionic acid
Otopina 1,37 g (19,7 mmol, 1,3 ekvivalenta) hidroksilamin hidroklorida u 9,2 ml (114 mmol, 7,5 ekvivalenata) suhog piridina pri 0 °C obrađuje se sa 5,8 ml (45 mmol, 3,0 ekvivalenta) trimetilsilil klorida, što uzrokuje taloženje bijele krutine, i ostavi da se ugrije do sobne temperature preko noći. Ova smjesa se zatim ohladi na 0 °C i obradi s otopinom 7,54 g (15,1 mmol) etilnog estera 3-{(1-klorokarbonilciklopentil)-[4-(4-fluorofenoksi)-benzensulfonil]amino}propionske kiseline u 73 ml diklormetana, pripremljenom kako je gore opisano, bez izolacije, što uzrokuje oslobađanje topline do 8 °C. Ova smjesa se miješa pri 0 °C 30 minuta i pri sobnoj temperaturi oko 1 sat. Reakcijska smjesa se zatim obrađuje sa 50 ml 2N vodene kloridne kiseline i miješa pri sobnoj temperaturi 1 sat. Vodena faza se ekstrahira s diklormetanom i sjedinjeni organski ekstrakti se isperu s 2N vodenom kloridnom kiselinom (2 × 50 ml) i vodom (50 ml). Ova otopina etilnog estera 3-[[4-(4-fluorofenoksi)benzensulfonil]-(1-hidroksikarbamoilciklopentil)amino]propionske kiseline u diklormetanu se upotrijebi za pripravu 3-[[4-(4-fluorofenoksi)benzensulfonil]-(1-hidroksi karbamoilciklopentil)amino]-propionske kiseline bez izolacije. Alikvot se ukoncentrira do spužvaste mase. A solution of 1.37 g (19.7 mmol, 1.3 equiv) of hydroxylamine hydrochloride in 9.2 ml (114 mmol, 7.5 equiv) of dry pyridine at 0 °C is treated with 5.8 ml (45 mmol, 3 .0 equiv) of trimethylsilyl chloride, causing a white solid to precipitate, and allowed to warm to room temperature overnight. This mixture was then cooled to 0 °C and treated with a solution of 7.54 g (15.1 mmol) of 3-{(1-chlorocarbonylcyclopentyl)-[4-(4-fluorophenoxy)-benzenesulfonyl]amino}propionic acid ethyl ester in 73 ml of dichloromethane, prepared as described above, without insulation, which causes the release of heat up to 8 °C. This mixture is stirred at 0 °C for 30 minutes and at room temperature for about 1 hour. The reaction mixture is then treated with 50 ml of 2N aqueous hydrochloric acid and stirred at room temperature for 1 hour. The aqueous phase was extracted with dichloromethane and the combined organic extracts were washed with 2N aqueous hydrochloric acid (2 x 50 ml) and water (50 ml). This solution of 3-[[4-(4-fluorophenoxy)benzenesulfonyl]-(1-hydroxycarbamoylcyclopentyl)amino]propionic acid ethyl ester in dichloromethane was used to prepare 3-[[4-(4-fluorophenoxy)benzenesulfonyl]-(1- hydroxy carbamoylcyclopentyl)amino]-propionic acid without isolation. The aliquot is concentrated to a spongy mass.
1H NMR (DMSO-d6) δ 10,37 (s, 1H); 8,76 (s, 1H); 7,74-7,79 (m, 2H); 7,24-7,30 (m, 2H); 7,14-7,20 (m, 2H); 7,01-7,05 (m, 2H); 3,99 (q, J=7,1 Hz, 2H); 3,42-3,47 (m, 2H); 2,62-2,67 (m, 2H); 2,16-2,23 (m, 2H); 1,77-1,85 (m, 2H); 1,43-1,52 (m, 4H); 1,13 (t, J=7,1 Hz, 3H). 1H NMR (DMSO-d6) δ 10.37 (s, 1H); 8.76 (s, 1H); 7.74-7.79 (m, 2H); 7.24-7.30 (m, 2H); 7.14-7.20 (m, 2H); 7.01-7.05 (m, 2H); 3.99 (q, J=7.1 Hz, 2H); 3.42-3.47 (m, 2H); 2.62-2.67 (m, 2H); 2.16-2.23 (m, 2H); 1.77-1.85 (m, 2H); 1.43-1.52 (m, 4H); 1.13 (t, J=7.1 Hz, 3H).
Slično pripremljena otopina se ukoncentrira u vakuumu do 6,71 g (89 %) etilnog estera 3-[[4-(4-fluorofenoksi)benzensulfonil]-(1-hidroksikarbamoilciklopentil)amino]propionske kiseline kao tvrde suhe spužvaste mase. A similarly prepared solution is concentrated in vacuo to 6.71 g (89 %) of 3-[[4-(4-fluorophenoxy)benzenesulfonyl]-(1-hydroxycarbamoylcyclopentyl)amino]propionic acid ethyl ester as a hard dry spongy mass.
H) [[4-(4-fluorofenoksi)benzensulfonil]-(1-hidroksikarbamoilciklopentil)amino]propionska kiselina H) [[4-(4-fluorophenoxy)benzenesulfonyl]-(1-hydroxycarbamoylcyclopentyl)amino]propionic acid
Otopina 7,48 g (15,1 mmol) etilnog estera 3-[[4-(4-fluorofenoksi)benzensulfonil]-(1-hidroksikarbamoil-ciklopentil)amino]propionske kiseline u diklormetanu ukoncentrira se rotirajućom evaporacijom uz dodatak 75 ml toluena. Ova otopina se obrađuje se 75 ml vode, ohladi na 0 °C, i zatim obrađuje sa 6,05 g (151 mmol, 10 ekvivalenata) peleta natrij-hidroksida tijekom 10 minuta uz snažno miješanje. Ova smjesa se miješa 15 minuta pri 0 °C i ugrije do sobne temperature tijekom 1 sata. Vodena faza se odijeli, razrijedi sa 7,5 ml tetrahidrofurana, ohladi na 0 °C, i obrađuje sa 33 ml 6N vodene kloridne kiseline tijekom 20 minuta. Ova smjesa se miješa sa 75 ml etil-acetata pri 0 °C do sobne temperature, i etil-acetatna faza se odijeli i ispere vodom. Etil-acetatna otopina se polako obrađuje sa 150 ml heksana pri sobnoj temperaturi što uzrokuje taloženje krutine, i miješa preko noći. Filtracijom se dobiva 5,01 g 3-[[4-(4-fluorofenoksi) benzensulfonil]-(1-hidroksikarbamoilciklopentil)amino]propionske kiseline kao bijele krutine (71 % prinosa od 1-{(2-etoksikarboniletil)-[4-(4-fluorofenoksi)benzensulfonil]amino}ciklopentan karboksilne kiseline). A solution of 7.48 g (15.1 mmol) of 3-[[4-(4-fluorophenoxy)benzenesulfonyl]-(1-hydroxycarbamoyl-cyclopentyl)amino]propionic acid ethyl ester in dichloromethane is concentrated by rotary evaporation with the addition of 75 ml of toluene. This solution was treated with 75 ml of water, cooled to 0 °C, and then treated with 6.05 g (151 mmol, 10 equivalents) of sodium hydroxide pellets for 10 min with vigorous stirring. This mixture was stirred for 15 minutes at 0 °C and warmed to room temperature over 1 hour. The aqueous phase is separated, diluted with 7.5 ml of tetrahydrofuran, cooled to 0 °C, and treated with 33 ml of 6N aqueous hydrochloric acid for 20 minutes. This mixture is stirred with 75 ml of ethyl acetate at 0 °C to room temperature, and the ethyl acetate phase is separated and washed with water. The ethyl acetate solution is slowly treated with 150 ml of hexane at room temperature causing a solid to precipitate, and stirred overnight. Filtration gives 5.01 g of 3-[[4-(4-fluorophenoxy)benzenesulfonyl]-(1-hydroxycarbamoylcyclopentyl)amino]propionic acid as a white solid (71% yield from 1-{(2-ethoxycarbonylethyl)-[4- (4-fluorophenoxy)benzenesulfonyl]amino}cyclopentane carboxylic acids).
1H NMR (DMSO-d6) δ 12,32 (s, 1H); 10,43 (s, 1H); 8,80 (s, 1H); 7,82 (d, J=8,6 Hz, 2H); 7,28-7,35 (m, 2H); 7,20-7,26 (m, 2H); 7,08 (d, J=8,9 Hz, 2H); 3,44-3,49 (m, 2H); 2,61-2,66 (m, 2H); 2,24-2,29 (m, 2H); 1,86-1,90 (m, 2H); 1,54-1,55 (m, 4H). Talište 162,9-163,5 °C (deklarirano). 1H NMR (DMSO-d6) δ 12.32 (s, 1H); 10.43 (s, 1H); 8.80 (s, 1H); 7.82 (d, J=8.6 Hz, 2H); 7.28-7.35 (m, 2H); 7.20-7.26 (m, 2H); 7.08 (d, J=8.9 Hz, 2H); 3.44-3.49 (m, 2H); 2.61-2.66 (m, 2H); 2.24-2.29 (m, 2H); 1.86-1.90 (m, 2H); 1.54-1.55 (m, 4H). Melting point 162.9-163.5 °C (declared).
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AT (1) | ATE233729T1 (en) |
AU (1) | AU758297B2 (en) |
BG (1) | BG103321A (en) |
BR (1) | BR9902041A (en) |
CA (1) | CA2268679C (en) |
CO (1) | CO4810300A1 (en) |
DE (1) | DE69905633T2 (en) |
DK (1) | DK0949246T3 (en) |
DZ (1) | DZ2755A1 (en) |
EA (1) | EA001756B1 (en) |
ES (1) | ES2192021T3 (en) |
GT (1) | GT199900044A (en) |
HR (1) | HRP990107B1 (en) |
HU (1) | HU221635B1 (en) |
ID (1) | ID23645A (en) |
IL (1) | IL129330A (en) |
IN (1) | IN191233B (en) |
IS (1) | IS5020A (en) |
MA (1) | MA24834A1 (en) |
NO (1) | NO991679L (en) |
NZ (1) | NZ335106A (en) |
OA (1) | OA11032A (en) |
PA (1) | PA8469801A1 (en) |
PE (1) | PE20000416A1 (en) |
PL (1) | PL332452A1 (en) |
SG (1) | SG75169A1 (en) |
SI (1) | SI0949246T1 (en) |
SK (1) | SK44999A3 (en) |
TN (1) | TNSN99051A1 (en) |
TR (1) | TR199900757A2 (en) |
TW (1) | TW539664B (en) |
UA (1) | UA59373C2 (en) |
UY (1) | UY25472A1 (en) |
YU (1) | YU18299A (en) |
ZA (1) | ZA992628B (en) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6458822B2 (en) | 2000-03-13 | 2002-10-01 | Pfizer Inc. | 2-oxo-imidazolidine-4-carboxylic acid hydroxamide compounds that inhibit matrix metalloproteinases |
US7629341B2 (en) * | 2002-06-12 | 2009-12-08 | Symphony Evolution, Inc. | Human ADAM-10 inhibitors |
EP1594459B1 (en) | 2002-12-30 | 2010-02-17 | Angiotech International Ag | Drug delivery from rapid gelling polymer composition |
EP2590951B1 (en) | 2010-07-09 | 2015-01-07 | Pfizer Limited | Benzenesulfonamides useful as sodium channel inhibitors |
Family Cites Families (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE844004C (en) * | 1944-08-06 | 1952-07-14 | Cassella Farbwerke Mainkur Ag | Process for the production of sulfonic acid esters |
US4032506A (en) * | 1973-12-28 | 1977-06-28 | General Electric Company | Flame retardant polycarbonate composition |
ZA794723B (en) * | 1978-09-11 | 1980-08-27 | Univ Miami | Anti-hypertensive agents |
GB9000725D0 (en) * | 1990-01-12 | 1990-03-14 | Pfizer Ltd | Therapeutic agents |
US5340489A (en) * | 1992-06-05 | 1994-08-23 | The Dow Chemical Company | Aryl arenesulfonates and a method of lubrication using the aryl arenesulfonates |
US5863949A (en) * | 1995-03-08 | 1999-01-26 | Pfizer Inc | Arylsulfonylamino hydroxamic acid derivatives |
PL331895A1 (en) * | 1996-08-23 | 1999-08-16 | Pfizer | Arylosulphonylamino derivatives of hydroxamic acid |
ID22799A (en) * | 1997-02-03 | 1999-12-09 | Pfizer Prod Inc | ARILSULFONILAMINO HYDROCSAMATE ACID DRIVINGS |
WO1998050348A1 (en) * | 1997-05-09 | 1998-11-12 | Agouron Pharmaceuticals, Inc. | Metalloproteinase inhibitors, pharmaceutical compositions containing them and their pharmaceutical uses |
DK0895988T3 (en) * | 1997-08-08 | 2002-09-09 | Pfizer Prod Inc | arylsulfonylamino hydroxamic acid |
TR200000368T2 (en) * | 1997-08-08 | 2000-07-21 | Pfizer Products Inc. | Ariloxyariarylsulfonylamino hydroxamic acid derivatives. |
PA8469401A1 (en) * | 1998-04-10 | 2000-05-24 | Pfizer Prod Inc | BICYCLE DERIVATIVES OF HYDROXAMIC ACID |
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1999
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2000
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